The porphyrins and related tetrapyrrole macrocycles are among the most versatile of tetradentate ligands.sup.1 (see Example 1 for the references in this paragraph). Attempts to stabilize higher coordination geometries, however, with larger porphyrin-like aromatic macrocycles have met with little success..sup.2-5 Indeed, to date, only the uranyl complex of "superphthalocyanine" has been isolated and characterized structurally,.sup.2 although several other large porphyrin-like aromatic macrocycles, including the "sapphyrins",.sup.3,6 "oxosapphyrins",.sup.6,7 "platyrins",.sup.8 "pentaphyrin",.sup.9 and "[26]porphyrin",.sup.10 have been prepared in their metal free forms.
Although the porphyrins and related tetrapyrrolic compounds remain among the most widely studied of all known macrocycles,.sup.1 relatively little effort has been devoted to the development of larger conjugated pyrrole containing systems.sup.2-12 (references cited in this paragraph are shown in Example 2). Large, or "expanded" porphyrin-like systems, however, are of interest for several reasons: They could serve as possible aromatic analogues of the better studied porphyrins.sup.2-8 or serve as potential biomimetic models for these or other naturally occurring pyrrole-containing systems..sup.13,14 In addition, large pyrrole containing systems offer exciting possibilities as novel metal binding macrocycles..sup.2,9-12,15 For instance, suitably designed systems could act as versatile ligands capable of binding larger metal cations and/or stabilizing higher coordination geometries.sup.2,16 than those routinely accommodated within the normally tetradentate ca. 2.0 .ANG. radius porphyrin core..sup.17 The resulting complexes could have important application in the area of heavy metal chelation therapy, serve as contrast agents for magnetic resonanace imaging (MRI) applications, act as vehicles for radioimmunological labeling work, or serve as new systems for extending the range and scope of coordination chemistry..sup.15,18 In addition, the free-base (metal-free) and/or diamagnetic metal-containing materials could serve as useful photosensitizers for photodynamic therapeutic applications. In recent years a number of potentially pentadentate polypyrrolic aromatic systems, including the "sapphyrins",.sup.3,4 "oxosapphyrins",.sup.5 "smaragdyrins",.sup.3,4 platyrins.sup.6 and "pentaphyrin" .sup.7 have been prepared and studied as their metal-free forms. For the most part, however, little or no information is available for the corresponding metallated forms. Indeed, the uranyl complex of "superphthalocyanine " was the only metal-containing pentapyrrolic system which has been prepared and characterized structurally..sup.2 Unfortunately, the "superphthalocyanine" system is apparently not capable of existence in either its free-base or other metal-containing forms..sup.2 Thus, prior to the present invention, no versatile, structurally characterized, pentadentate aromatic ligands were available,.sup.11 although a number of nonaromatic pyridine-derived pentadentate systems had previously been reported..sup.19,20
Gadolinium(III) complexes derived from strongly binding anionic ligands, such as diethylenetriamine pentaacetic acid (DTPA),.sup.1,2,3 1,4,7,10-tetraazacyclododecane N,N',N, ",N'"-tetraacetic acid (DOTA),.sup.1,4,5 and 1,10-diaza-4,7,13,16-tetraoxacyclooctadecane-N,N'-diacetic acid (dacda),.sup.1,6 are among the most promising of the paramagnetic contrast currently being developed for use in magnetic resonance imaging (MRI).sup.1 (references cited in this paragraph are shown in Example 3). Indeed, [Gd. DTPA].sup.- is now undergoing clinical trials in the United States for possible use in enhanced tumor detection protocols..sup.1 Nonetheless, the synthesis of other gadolinium(III) complexes remains of interest since such systems might have greater kinetic stability, superior relaxivity, or better biodistribution properties than the existing carboxylate-based contrast agents. One approach currently being pursued is based on using water-soluble porphyrin derivatives, such as tetrakis(4-sulfonatophenyl)porphyrin (TPPS)..sup.7,8,9 Unfortunately, the large gadolinium(III) cation cannot be accommodated completely.sup.10 within the relatively small prophyrin binding core (r.congruent.2.0 .ANG..sup.11), and, as a consequence, gadolinium prophyrin complexes are invariably hydrolytically unstable..sup.7,8,12,13 Larger porphyrin-like ligands, however, might offer a means of circumventing this problem..sup.14-22
Acquired immunodeficiency syndrome (AIDS) and cancer are among the most serious public health problems facing our nation today. AIDS, first reported in 1981 as occurring among male homosexuals,.sup.1 is a fatal human disease which has now reached pandemic proportions (the references in this and the following four paragraphs are shown in Example 5). Cancer, in spite of some very significant advances in diagnostics and treatment in recent years, remains the third leading cause of death in this country. Finding better ways to detect, treat, and reduce the transmission of these disorders are thus research objectives of the highest importance.
One of the more promising new modalities currently being explored for use in the control and treatment of tumors is photodynamic therapy (PDT)..sup.1-5 This technique is based on the use of a photosensitizing dye, which localizes at, or near, the tumor site, and when irradiated in the presence of oxygen serves to produce cytotoxic materials, such as singlet oxygen (O.sub.2 (.sup.1 .DELTA..sub.g)), from otherwise benign precursors (e.g. (O.sub.2 (.sup.3 .SIGMA..sub.g -)). Much of the current excitement associated with PDT derives from
just this property: In marked contrast to current methods (e.g. conventional chemotherapy), in PDT the drugs themselves can (and should) be completely innocuous until "activated" with light by an attending physician. Thus a level of control and selectivity may be attained which is not otherwise possible.
At present, diamagnetic porphyrins and their derivatives are considered the dyes of choice for PDT. It has been known for decades that porphyrins, such as hematoporphyrin, localize selectively in rapidly growing tissues including sarcomas and carcinomas,.sup.6 although the reasons for this selectivity remain recondite. Currently most attention is focusing on the so-called hematoporphyrin derivative (HPD),.sup.2-5,7-21 an incompletely characterized mixture of monomeric and oligomeric porphyrins produced by treating hematoporphyrin dihydrochloride with acetic acid-sulfuric acid followed by dilute base..sup.22,27 Fractions rich in the oligomeric species, which are believed to have the best tumor-localizing ability,.sup.23,26 are marketed under the trade name Photofirin II.RTM. (PII) and are currently undergoing phase III clinical trials for obstructed endobronchial tumors and superficial bladder tumors. Here, the mechanism of action is thought to be largely, if not entirely, due to the photoproduction of singlet oxygen (O.sub.2 (.sup.1 .DELTA..sub.g)), although alternative mechanisms of action, including those involving superoxide anion or hydroxyl and/or porphyrin-based radicals cannot be entirely ruled out..sup.28-33 Promising as HPD is, it and other available photosensitizers (e.g., the phthalocyanines and napthaphthalocynines) suffer from serious disadvantages.
While porphyrin derivatives have high triplet yields and long triplet lifetimes (and consequently transfer excitation energy efficiently to triplet oxygen),.sup.3b,3g their absorption in the Q-band region often parallels that of heme-containing tissues. Phthalocyanines and naphthalocyanines absorb in a more convenient spectral range but have significantly lower triplet yields;.sup.4 moreover, they tend to be quite insoluble in polar protic solvents, and are difficult to functionalize. Thus at present the development of more effective photochemotherapeutic agents appears to require the synthesis of compounds which absorb in the spectral region where living tissues are relatively transparent (i.e., 700-1000 nm),.sup.1d have high triplet quantum yields, and are minimally toxic. The present inventors have recently reported.sup.5 (see Example 1) the synthesis of a new class of aromatic porphyrin-like macrocycles, the tripyrroledimethine-derived "texaphyrins", which absorb strongly in the tissue-transparent 730-770 nm range. The photophysical properties of metallotexaphyrins 1.sub.C -7.sub.C parallel those of the corresponding metallaporphyrins and the diamagnetic complexes 1.sub.C -4.sub.C sensitize the production of .sup.1 O.sub.2 in high quantum yield. FIG. 19 shows the schematic structure, metal complexes and derivatives of compounds of the present invention (1.sub.C -7.sub.C).
Singlet oxygen is also believed to be the critical toxic species operative in experimental photsensitized blood purification procedures..sup.34-39 This very new application of photodynamic therapy is of tremendous potential importance: It shows promise of providing a safe and effective means of removing enveloped viruses such as HIV-1, herpes simplex (HSV), cytomegalovirus (CMV), various forms of hepatitis-inducing virus, as well as other opportunistic blood-borne infections (e.g. bacteria and malaria-plasmodium) from transfused whole blood. Given that AIDS is currently a not effectively treated and usually fatal disease, the benefit of such a blood purification procedure would be of inestimable value.
At present, sexual relations and needle-sharing are the dominant mechanisms for the spread of AIDS..sup.1 An increasing percentage of AIDS infections, however, are now occurring as a result of blood transfusions..sup.1,40-43 Unfortunately, banked blood components are essential products for the practice of modern medicine and as a result this method of transmission is not likely to be precluded by simple changes in lifestyle. Rather, an absolutely fail-proof means must be developed to insure that all stored blood samples are free of the AIDS virus (and ideally all other blood-borne pathogens). To a certain extent this can be accomplished by screening the donors' histories and carrying out serologic tests. At present, however, the serologic tests for HIV-1 are insufficient to detect all infected blood samples, in particular, those derived from donors who have contacted the disease but not yet produced detectable antibodies..sup.42,43 In addition, new mutants of the AIDS virus have been detected; some or all of which may escape detection by current means..sup.1 Thus, an antiviral system is needed which removes any form of HIV-1 from stored blood. This is particularly important since a stored blood sample from one infected donor could potentially end up being administered to several different patients, in, for instance, the course of pediatric care.